Cause of Alzheimer's amyloid damage found: Scripps study

Point Loma  A previously unknown cause of the brain damage from Alzheimer’s disease has been discovered by scientists at The Scripps Research Institute, according to a study published Wednesday.

Researchers not involved in the study say it may help guide development of drugs against the neurodegenerative disease — an effort scarred by expensive failures. The study was performed in a mouse model of the disease.

The research clarifies the role of a protein called amyloid beta, long suspected in Alzheimer’s disease. It demonstrated that other factors besides the protein trigger the disease’s characteristic neural damage.

The study, published in the journal Neuron, was led by Scripps professor Franck Polleux. The first author was Georges Mairet-Coello, a researcher in the Polleux lab.

The study described a relationship between three distinctive changes found in Alzheimer’s:

• Amyloid beta causes overactivity of an enzyme called AMPK.

• The overactivation causes neurons to accumulate a modified version of the protein tau, also long implicated in Alzheimer’s.

• Early in the disease, amyloid beta leads to loss of synapses, the small gaps over which signals travel between neurons.

The enzyme’s role in synapse loss was previously unknown, Polleux said.

Franck Polleux, a professor at The Scripps Research Institute in La Jolla.— The Scripps Research Institute

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Franck Polleux, a professor at The Scripps Research Institute in La Jolla.
/ The Scripps Research Institute

Most importantly, when researchers blocked the enzyme’s overactivity in the Alzheimer’s mouse model, the synapse loss was prevented. This demonstrated that the enzyme played a causal role in the disease changes, Polleux said.

For decades, Alzheimer’s drugs have been developed to remove amyloid beta plaques from neurons. While they have succeeded in that goal, none have blocked or even significantly slowed the disease’s progress. These failures have led scientists to question whether the “amyloid” hypothesis” of Alzheimer’s is wrong.

The Scripps study indicates that the hypothesis is correct, but incomplete. The study demonstrated that other substances besides amyloid beta can cause the enzyme overactivation.

These include metformin, a commonly used drug for Type 2 diabetes. The disease is a known risk factor for Alzheimer’s. The study suggested more research to judge the safety of long-term use of metformin.

The study was partly funded by the National Institutes of Health and by the Swiss drug company Novartis.

Bob Zeller, a researcher at San Diego State University who has studied amyloid plaques, said the study “gives a molecular explanation” about what amyloid beta does. This explains both the association with the disease and why targeting the protein alone isn’t effective.

Greg M. Cole, associate director for the UCLA Alzheimer’s Center, said the study indicates Alzheimer’s may best be treated with drugs that target multiple mechanisms that lead to the disease. However, such multiple-effect drugs aren’t favored by U.S. regulators, who prefer simple explanations.

“They’ve been telling people, show us the mechanism,” Cole said. “More mechanisms makes it more complicated. Their argument for safety has been to go for the highest-affinity drug, that hits only one pathway, the idea being that hitting that pathway will make it safe.”

That approach doesn’t necessarily work in a disease like Alzheimer’s in which several processes go wrong, Cole said.

Cole cautioned that because the study was performed in mice, its applicability to humans isn’t confirmed.